The present invention relates to a novel production method of an oxazole compound of the formula [7] having a selective inhibitory action on cyclooxygenase-2 (COX-2) 
wherein R1 is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, R2 is a lower alkyl or a halogenated lower alkyl, and R3 is a halogen atom or a hydrogen atom. The present invention also relates to a method for producing intermediates for the production of a compound of the above-mentioned formula [7].
The above-mentioned compound [7], which selectively inhibits cyclooxygenase-2 (COX-2), is useful as, for example, an antiinflammatory agent. The production method of compound [7] has been already disclosed in the specification of WO96/19463.
However, the conventional production methods require many treatment steps and the yields of the final product and intermediates therefor are not entirely satisfactory. In addition, the reagent, solvent and the like to be used in each step suffice for use only at laboratory levels and many of them are problematically impractical and cannot be used in industrial production.
The present inventors have studied respective steps in detail and improved them. To be specific, they considered the production method (hereinafter to be referred to as method A) disclosed in WO96/19463, which is most similar to the present invention.
According to the method A, compound [7xe2x80x2], which is one of the objective compounds of the present invention, is produced by the following Steps 1-4. 
Step 1
According to method A, compound [1xe2x80x2] is reacted with ethyl chlorocarbonate in ethyl acetate in the presence of triethylamine to give compound [2xe2x80x2]. When ethyl chlorocarbonate is used as a reagent in this step, ethanol is generated as a by-product and decomposes compound [2xe2x80x2]. To prevent this, a complicated post-treatment such as desalting filtration and concentration is needed after the main reaction, cyclization. Thus, method A is associated with a complicated post-treatment and lower yield of compound [2xe2x80x2] due to the generation of the by-product. The present inventors considered using economical thionyl chloride instead of ethyl chlorocarbonate to solve this problem. As a result, they have found that the use of thionyl chloride obliterates the above-mentioned complicated post-treatment and generation of the by-product, which has led to an improvement in the yield. It has been also found that the unstable compound [2xe2x80x2] can be used in the next step without isolation or purification. These improvements have achieved an increase in the yield.
Step 2
In method A, compound [2xe2x80x2] is reacted with compound [3xe2x80x2] in a tetrahydrofuran suspension of magnesium chloride in the presence of triethylamine to give compound [4xe2x80x2]. Tetrahydrofuran used as a reagent and solvent in this step is not a most suitable solvent in terms of cost, when industrially used in a large amount. Thus, the present inventors have studied solvents to find out a solvent economical and suitable for industrial production, as well as from the aspect of an improved yield. Consequently, they have found that ethyl acetate, which is recited in the specification of WO96/19463 as a general example but is not specifically disclosed as an example, can be used to conduct this reaction similarly. This change of solvent offers merits of not only low cost but omission of concentration of the reaction solvent before extraction in the next step (Step 3). This has offered a simultaneous resolution to the problems of reduction of cost and increase in yield. In addition, they have found that the unstable compound [4xe2x80x2] can be used in the next step without isolation or purification. These improvements resulted in an increased yield.
Step 3
In method A, hydrochloric acid is added to compound [4xe2x80x2] in tetrahydrofuran to allow hydrolysis and decarboxylation. Subsequently, compound [5xe2x80x2] is obtained through post-treatment of concentration of the reaction solvent (tetrahydrofuran), extraction, concentration of the extraction solvent and the like. The present inventors changed tetrahydrofuran, the solvent used in the previous step (Step 2), to ethyl acetate and conducted Step 3 in ethyl acetate, whereby they have succeeded in omitting a step for concentration of tetrahydrofuran before extraction. This has led to the improved yield of compound [5xe2x80x2].
When compared in the yields of Compound [5xe2x80x2] from compound [1xe2x80x2], it was 67.7% by method A but 84.7% by the present invention, thus achieving a 17% increase in the yield.
Step 4
In method A, compound [5xe2x80x2] is reacted with chlorosulfonic acid in chloroform to give compound [6xe2x80x2]. Further, by reacting this compound with aqueous ammonia in tetrahydrofuran without isolation, objective compound [7xe2x80x2] is obtained. The solvent used here is chloroform, which has strong toxicity and is problematic for industrial use. The present inventors have overcome this problem by the use of a method generally exemplified in the specification of WO96/19463 but not specifically shown as an example. Surprisingly, the reaction was found to proceed as smoothly as when chloroform was used, even without a solvent.
The method A is not satisfactory in terms of the yield of the objective compound [7xe2x80x2]. According to method A, compound [7xe2x80x2] is obtained through a post-treatment of concentration of the reaction solvent (tetrahydrofuran), extraction, concentration of the extraction solvent and the like. Like Step 2, the present inventors changed the solvent for amidation from tetrahydrofuran to ethyl acetate to omit concentration of tetrahydrofuran before extraction.
This has led to the elimination of problems associated with the prior art technique, and the yield of compound [7xe2x80x2] from compound [5xe2x80x2] was increased by about 5% from 77.2% to 82.0%.
As mentioned above, the present inventors studied the problems in each step in detail with the aim of improving the yield of the objective compound and establishing the method capable of affording industrial production, and they have found that the use of the above-mentioned solvent, reagent and the like in each step results in the production of the objective compound at a high yield and also an industrially practical production method, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following (1) to (9).
(1) A production method of an oxazole compound of the formula [7]
wherein R1 is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, R2 is a lower alkyl or a halogenated lower alkyl and R3 is a halogen atom or a hydrogen atom, comprising reacting a compound of the formula [1]
wherein R1 and R2 are as defined above, with thionyl chloride in an inert solvent in the presence of a base, to give an oxazolone compound of the formula [2]
wherein R1 and R2 are as defined above, subsequently reacting this compound with a compound of the formula [3]
wherein R3 is as defined above and X is a halogen atom, in ethyl acetate in the presence of a magnesium salt and a base to give a compound of the formula [4]
wherein R1, R2 and R3 are as defined above, subjecting this compound to hydrolysis and decarboxylation with an acid to give a compound of the formula [5]
wherein R1, R2 and R3 are as defined above, subjecting this compound to cyclization and sulfonation with a sulfonating agent and chlorination with thionyl chloride to give a compound of the formula [6]
wherein R1, R2 and R3 are as defined above, and subjecting this compound to amidation in ethyl acetate with aqueous ammonia.
(2) The method of (1) wherein R1 is a cycloalkyl, R2 is a lower alkyl, and R3 is a halogen atom.
(3) The method of (1) wherein R1 is a cyclohexyl, R2 is a methyl, and R3 is a fluorine atom.
(4) A production method of an acetophenone compound of the formula [5]
wherein R1 is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, R2 is a lower alkyl or a halogenated lower alkyl and R3 is a halogen atom or a hydrogen atom, comprising reacting a compound of the formula [1]
wherein R1 and R2 are as defined above, with thionyl chloride in an inert solvent in the presence of a base to give an oxazolone compound of the formula [2]
wherein R1 and R2 are as defined above, sequentially reacting this compound with a compound of the formula [3]
wherein R3 is as defined above and X is a halogen atom, in ethyl acetate in the presence of a magnesium salt and a base to give a compound of the formula [4]
wherein R1, R2 and R3 are as defined above, and subjecting this compound to hydrolysis and decarboxylation with an acid.
(5) The method of (4) wherein R1 is a cycloalkyl, R2 is a lower alkyl, and R3 is a halogen atom.
(6) The method of (4) wherein R1 is a cyclohexyl, R2 is a methyl, and R3 is a fluorine atom.
(7) A production method of an oxazole compound of the formula [7]
wherein R1 is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, R2 is a lower alkyl or a halogenated lower alkyl and R3 is a halogen atom or a hydrogen atom, comprising subjecting a compound of the formula [5]
wherein R1, R2 and R3 are as defined above, to cyclization and sulfonation with a sulfonating agent, and chlorination with thionyl chloride to give a compound of the formula [6]
wherein R1, R2 and R3 are as defined above, and then subjecting this compound to amidation in ethyl acetate with aqueous ammonia.
(8) The method of (7) wherein R1 is a cycloalkyl, R2 is a lower alkyl, and R3 is a halogen atom.
(9) The method of (7) wherein R1 is a cyclohexyl, R2 is a methyl, and R3 is a fluorine atom.
Each substituent used in the present specification are defined as follows.
The cycloalkyl group is that having 3 to 8 carbon atoms, which is specifically exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferred is cycloalkyl group having 5 to 7 carbon atoms. Specific examples thereof include cyclopentyl, cyclohexyl and cycloheptyl, where particularly preferred is cyclohexyl.
The heterocyclic group is a 5- or 6-membered aromatic heterocycle, saturated heterocycle, unsaturated heterocycle, or condensed heterocycle wherein such heterocycle and a benzene ring or cyclohexane ring are condensed, which has, as an atom constituting the ring, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, besides carbon atom. Specific examples thereof include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, morpholino, morpholinyl, piperazinyl, piperidyl, pyranyl, thiopyranyl, pyridyl, benzothienyl, benzofuranyl, indolyl, 4,5,6,7-tetrahydroindolyl, 4,5,6,7-tetrahydrobenzothienyl, 4,5,6,7-tetrahydrobenzofuranyl and the like. Preferred are thienyl, furyl, pyrrolyl, morpholino, morpholinyl, piperazinyl and piperidyl, and particularly preferred is thienyl.
The aryl group is, for example, phenyl, naphthyl, biphenylyl and the like, with preference given to phenyl.
The xe2x80x9coptionally substitutedxe2x80x9d means that the group may be substituted by 1 to 3 substituents which may be the same or different. The position of the substituent is optional and subject to no particular limitation. Specific examples thereof include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like; hydroxy; lower alkoxy such as methoxy, ethoxy, propoxy, butoxy and the like; halogen atom such as fluorine, chlorine, bromine and the like; nitro; cyano; acyl (e.g., formyl, or lower alkylcarbonyl such as acetyl, propionyl and the like); acyloxy such as formyloxy, acetyloxy, propionyloxy and the like (acyl moiety being as defined above); mercapto; lower alkylthio such as methylthio, ethylthio, propylthio, butylthio, isobutylthio and the like; amino; lower alkylamino such as methylamino, ethylamino, propylamino, butylamino and the like; di(lower)alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino and the like; carboxy; lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like; amido; trifluoromethyl; lower alkylsufonyl such as methylsulfonyl, ethylsulfonyl and the like; aminosulfonyl; lower cycloalkyl such as cyclopentyl, cyclohexyl and the like; phenyl; and acylamino such as acetamido, propionamido and the like (acyl moiety being as defined above), with preference given to hydroxy, lower alkyl, lower alkoxy, mercapto, lower alkylthio, halogen atom, trifluoromethyl, lower alkylcarbonyl, lower alkoxycarbonyl and acylamino. As used herein, by lower is meant that the number of carbon atoms is preferably 1 to 6, more preferably 1 to 4.
More specifically, the xe2x80x9coptionally substituted aryl groupxe2x80x9d means aryl group, particularly phenyl group optionally substituted by halogen atom, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl, aminosulfonyl and the like. Specific examples thereof include phenyl, fluorophenyl, methylphenyl, methoxyphenyl, methylsulfonylphenyl, aminosulfonylphenyl and the like, preferably phenyl and 4-fluorophenyl.
The xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d is heterocyclic group optionally substituted by halogen atom, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl, aminosulfonyl and the like, with preference given to thienyl, furyl, 5-methylthienyl and 5-chlorothienyl.
The xe2x80x9coptionally substituted cycloalkyl groupxe2x80x9d is cycloalkyl group optionally substituted by halogen atom, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl, aminosulfonyl and the like, with preference given to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-hydroxycyclohexyl, 4-fluorocyclohexyl and the like, particularly preferably cyclohexyl.
The xe2x80x9clower alkylxe2x80x9d is linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, tert-pentyl, hexyl and the like, which is preferably methyl.
The xe2x80x9chalogen atomxe2x80x9d means chlorine atom, bromine atom, fluorine atom and the like, with preference given to chlorine atom and fluorine atom. At R3, it is preferably fluorine atom and at X, it is preferably chlorine atom.
The xe2x80x9chalogenated lower alkylxe2x80x9d is the above-mentioned lower alkyl substituted by the above-mentioned halogen atom. Specific examples thereof include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, fluoroethyl, chloroethyl, difluoroethyl, dichloroethyl, trifluoroethyl, trichloroethyl, tetrachloroethyl, pentafluoroethyl, fluoropropyl and the like, with preference given to fluoromethyl, chloromethyl, dichloromethyl, difluoromethyl, trichloromethyl and trifluoromethyl.
The xe2x80x9cinert solventxe2x80x9d means ethyl acetate, tetrahydrofuran, toluene, dichloromethane and the like, preferably ethyl acetate.
The xe2x80x9cbasexe2x80x9d is a tertiary amine such as triethylamine, pyridine, N-methylmorpholine and the like; secondary amine such as diethylamine, diisopropylamine and the like; and inorganic base such as potassium carbonate, sodium carbonate and the like, with preference given to tertiary amine, which is more preferably triethylamine.
The xe2x80x9cmagnesium saltxe2x80x9d means anhydrous magnesium chloride, anhydrous magnesium bromide and the like, which is preferably anhydrous magnesium chloride.
The xe2x80x9cacidxe2x80x9d means hydrochloric acid, oxalic acid;, diluted sulfuric acid, phosphoric acid and the like, which is preferably hydrochloric acid.
The xe2x80x9csulfonating agentxe2x80x9d means chlorosulfonic acid, anhydrous sulfuric acid, concentrated sulfuric acid, fuming sulfuric acid and the like, which is preferably chlorosulfonic acid.
The production method of oxazole compound of the formula [7] is described in detail in the following. 
wherein R1, R2, R3 and X are as defined above.
General Production Method
Step 1
Compound [1] is reacted with thionyl chloride in an inert solvent in the presence of a base to give compound [2].
The inert solvent to be used for the reaction is ethyl acetate, tetrahydrofuran, toluene, dichloromethane and the like, which is preferably ethyl acetate.
Specific examples of the base include tertiary amine such as triethylamine, pyridine, N-methylmorpholine and the like; secondary amine such as diethylamine, diisopropylamine and the like; and inorganic base such as potassium carbonate, sodium carbonate and the like, with preference given to tertiary amine, which is more preferably triethylamine.
The reaction temperature is xe2x88x9220xc2x0 C. to 20xc2x0 C., preferably xe2x88x9210xc2x0 C. to 0xc2x0 C.
The reaction time is 0.5-10 hours, preferably 0.5-2 hours.
When this reaction is carried out, the reaction preferably proceeds under an inert gas atmosphere (e.g., nitrogen) to prevent reduction in the yield due to contamination with water.
The obtained compound [2] can be used in the next reaction without isolation.
Step 2
Compound [2] is reacted with compound [3] in ethyl acetate in the presence of a magnesium salt and a base to give compound [4].
As the magnesium salt, anhydrous magnesium chloride, anhydrous magnesium bromide and the like, preferably anhydrous magnesium chloride, can be used.
Examples of the base include tertiary amine such as triethylamine, pyridine, N-methylmorpholine and the like; secondary amine such as diethylamine, diisopropylamine and the like; and inorganic base such as potassium carbonate, sodium carbonate and the like, with preference given to tertiary amine, which is more preferably triethylamine.
The reaction temperature is xe2x88x9220xc2x0 C. to 20xc2x0 C., preferably 0xc2x0 C. to 10xc2x0 C.
The reaction time is 1-20 hours, preferably 6-15 hours.
This reaction is desirably carried out under an inert gas atmosphere, such as nitrogen as in Step 1, to prevent reduction in the yield due to contamination with water.
In this step, ether such as tetrahydrofuran, diethyl ether and the like, preferably tetrahydrofuran, is used as a reagent, which ensures smooth progress of the reaction. Ether is added in 2-5 equivalents, preferably 2 equivalents, relative to compound [2].
The obtained compound [4] can be used in the next reaction without isolation.
Step 3
Compound [4] is subjected to hydrolysis and decarboxylation with an acid to give compound [5].
This reaction preferably proceeds in a mixed solvent of ethyl acetate and water.
The acid to be used is exemplified by hydrochloric acid, oxalic acid, diluted sulfuric acid, phosphoric acid and the like, which is preferably hydrochloric acid.
The reaction temperature is xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 35xc2x0 C. to 45xc2x0 C.
The reaction time is 1-20 hours, preferably 1-3 hours.
Step 4
Compound [5] is subjected to cyclization and sulfonation with a sulfonating agent, and chlorination with thionyl chloride to give compound [6]. Sequentially, the product is, without isolation, reacted with aqueous ammonia in ethyl acetate to give the objective compound [7].
The reactions of cyclization and sulfonation are preferably carried out without solvent.
The sulfonating agent to be used is exemplified by chlorosulfonic acid, anhydrous sulfuric acid, concentrated sulfuric acid, fuming sulfuric acid and the like, which is preferably chlorosulfonic acid.
The temperature of the reaction to obtain compound [6] from compound [5] is 0xc2x0 C.-200xc2x0 C., preferably 75xc2x0 C.-95xc2x0 C. The time of the reaction of cyclization and sulfonation is 1-10 hours, preferably 2-5 hours. The reaction time of chlorination is 0.5-10 hours, preferably 0.5-5 hours.
In the reaction to obtain compound [6] from compound [5], the reaction is desirably carried out under an inert gas atmosphere, such as nitrogen as in Step 1, to prevent reduction in the yield due to contamination with water.
The temperature of the reaction to obtain compound [7] from compound [6] is xe2x88x9220xc2x0 C. to 200xc2x0 C., preferably xe2x88x9210xc2x0 C. to 10xc2x0 C. The reaction time is 1-24 hours, preferably 1-3 hours.